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Molecular association between β-catenin degradation complex and Rac guanine exchange factor DOCK4 is essential for Wnt/β-catenin signaling

Oncogene volume 27, pages 5845–5855 (2008)Cite this article

Abstract

The canonical Wnt/β-catenin pathway is a highly conserved signaling cascade that is involved in development and stem cell renewal. The deregulation of this pathway is often associated with increased cell growth and neoplasia. The small GTPase Rac has been shown to influence canonical Wnt signaling by regulating β-catenin stability through an unknown mechanism. We report that DOCK4, a guanine nucleotide exchange factor (GEF) for Rac and a member of the CDM family of unconventional GEFs, mediates Wnt-induced Rac activation in the canonical Wnt/β-catenin pathway. DOCK4 expression regulates cellular β-catenin levels in response to the Wnt signal, in vitro. Biochemical studies demonstrate that DOCK4 interacts with the β-catenin degradation complex, consisting of the proteins adenomatosis polyposis coli, Axin and glycogen synthase kinase 3β (GSK3β). This molecular interaction enhances β-catenin stability and Axin degradation. Furthermore, we observe that DOCK4 is phosphorylated by GSK3β, which enhances Wnt-induced Rac activation. Using a T-cell factor reporter zebrafish we confirm that DOCK4 is required for Wnt/β-catenin activity, in vivo. These results elucidate a novel intracellular signaling mechanism in which a Rac GEF, DOCK4 acts as a scaffold protein in the Wnt/β-catenin pathway.

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Acknowledgements

We thank Lars von Buchholtz (NIH, MD, USA), Parool Meelu (MGH, MA, USA), Tiffany M Blake (Georgetown University, DC, USA) and Denver Matthew Lough (Georgetown University, DC, USA) for the help in the preparation of the paper. This study was supported by grant NIH DK 63933 (VY) and MGH GI unit startup funds (VY).

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  1. G Upadhyay

    Present address: 3Current address: Dr G Upadhyay, Cancer Genetics, Georgetown University, Washington, DC 20007, USA. E-mail: gu6@georgetown.edu,

Authors and Affiliations

  1. Department of Medicine, Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    G Upadhyay, W Goessling, R Xavier & V Yajnik

  2. Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA

    W Goessling, T E North & L I Zon

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Correspondence to V Yajnik.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Upadhyay, G., Goessling, W., North, T. et al. Molecular association between β-catenin degradation complex and Rac guanine exchange factor DOCK4 is essential for Wnt/β-catenin signaling. Oncogene 27, 5845–5855 (2008). https://doi.org/10.1038/onc.2008.202

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